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Exposure to Methylphenidate During Infancy and Adolescence in Non-Human Animals and Sensitization to Abuse of Psychostimulants Later in Life: a Systematic Review

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Exposure to Methylphenidate During Infancy and Adolescence in Non-Human Animals and Sensitization to Abuse of Psychostimulants Later in Life: a Systematic Review Tin Psychiatryrends and Psychotherapy Review Article Exposure to methylphenidate during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review Exposição a metilfenidato na infância e adolescência em modelos não humanos e sensibilidade ao abuso de drogas psicoestimulantes na vida adulta: revisão sistemática Juliana Jaboinski,1,2 João Carlos Centurion Cabral,1 Renan Campos,2,3 Daniela Marti Barros2 Abstract Resumo Introduction: Attention deficit hyperactivity disorder (ADHD) is Introdução: O transtorno de déficit de atenção e hiperatividade a neuropsychiatric pathology that has an important prevalence (TDAH) é uma patologia neuropsiquiátrica de difícil diagnóstico e de among young people and is difficult to diagnose. It is usually tre- relevante prevalência entre pessoas jovens. É comumente tratada ated with methylphenidate, a psychostimulant with a mechanism com metilfenidato, uma substância psicoestimulante com meca- of action similar to that of cocaine. Previous studies show that nismo de ação similar ao da cocaína. Estudos prévios demonstram repeated use of psychostimulants during childhood or adolescence que o uso contínuo de fármacos estimulantes na infância ou ado- may sensitize subjects, making them more prone to later abuse lescência pode sensibilizar o sujeito para o subsequente abuso de of psychostimulant drugs such as cocaine and methamphetamine. drogas psicoestimulantes, como cocaína e metanfetamina. Objective: To review experimental studies in non-human mo- Objetivo: Revisar estudos experimentais em modelos não hu- dels (rodents and monkeys) treated with methylphenidate du- manos (roedores e macacos) tratados com metilfenidato na in- ring infancy or adolescence and tested for reinforcing effects on fância ou na adolescência e testados para os efeitos reforçadores psychostimulant drugs in adulthood. de drogas psicoestimulantes na vida adulta. Method: Systematic collection of data was performed on four Método: A coleta sistemática dos dados foi realizada em quatro databases (Web of Knowledge, PsycARTICLE, PubMed and SciE- bases de dados (Web of Knowledge, PsycARTICLE, PubMed e LO). The initial search identified 202 articles published from SciELO). Na busca inicial, 202 artigos publicados entre 2009 e 2009 to 2014, which were screened for eligibility. Seven articles 2014 foram triados. Destes, sete preencheram os critérios de met the inclusion criteria and were reviewed in this study. inclusão e foram revisados neste estudo. Results: The findings indicate that early exposure to methylphe- Resultados: Os dados indicam um efeito da pré-exposição ao nidate has an effect on an ADHD animal model, specifically, on metilfenidato sobre o TDAH em animais adolescentes da linha- spontaneously hypertensive strain rats, especially those tested gem do rato espontaneamente hipertensivo (spontaneously using the self-administration paradigm. hypertensive strain, SHR). Esse efeito foi encontrado, sobretudo, Conclusion: Future studies should prioritize the spontaneously nos estudos que utilizaram o paradigma de autoadministração. hypertensive rat strain – an animal model of ADHD. Experimen- Conclusão: Estudos futuros devem priorizar a linhagem dos SHR – tal designs comparing different behavioral paradigms and modes modelo animal do TDAH. Delineamentos que comparem diferentes of administration using this strain could lead to improved un- paradigmas comportamentais e formas de administração utilizando derstanding of the effects of exposure to methylphenidate during essa linhagem podem prover uma melhor compreensão do efeito childhood and adolescence. da exposição ao metilfenidato na infância e adolescência. Keywords: Methylphenidate, attention deficit hyperactivity di- Descritores: Metilfenidato, transtorno de déficit de atenção e hipe- sorder, animal models, analeptic drugs, drug abuse. ratividade, modelos animais, drogas analépticas, abuso de drogas. 1 Institute of Psychology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil. 2 Institute of Biological Sciences, Universidade Federal do Rio Grande (FURG), Rio Grande, RS, Brazil. 3 Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Université de Bordeaux, Bordeaux, France. Financial support: none. Submitted Dec 18 2014, accepted for publication Apr 25 2015. No conflicts of interest declared concerning the publication of this article. Suggested citation: Jaboinski J, Cabral JC, Campos R, Barros DM. Exposure to methylphenidate during infancy and adolescence in non-human animals and sensitization to abuse of psychostimulants later in life: a systematic review. Trends Psychiatry Psychother. 2015;37(3):107-117. http://dx.doi.org/10.1590/2237- 6089-2014-0060 APRS Trends Psychiatry Psychother. 2015;37(3) – 107-117 Methylphenidate exposure and stimulant abuse - Jaboinski et al. Introduction The pharmacological action of MPH is ascribed to blockage of dopamine (DA) and noradrenaline (NA) Stimulant drugs have been used to treat attention reuptake within the prefrontal cortex, thereby increasing deficit hyperactivity disorder (ADHD) for more than 70 the levels of both neurotransmitters in this region and years. This disorder is usually diagnosed in children and enhancing the functions for which they are responsible teenagers and may persist through adulthood.1 (attention, inhibitory control and working memory).1 Relevant concerns have been raised in recent decades Interestingly, cocaine also causes increased availability regarding the impact of chronic use of psychostimulants of DA, in particular in the dopaminergic mesolimbic such as methylphenidate (MPH) during brain development. pathway, which is known as the reward pathway in One pertinent point raised is the hypothesis that use of the brain. A large body of evidence suggests that this MPH during childhood and adolescence may sensitize action within the reward circuitry underlies the addictive the developing brain, eliciting susceptibility to drug properties of cocaine.6,8-10 Thus, both ADHD patients abuse (especially to psychostimulants) in adulthood.2 and people addicted to cocaine are likely to have a Considering the widespread use of this drug, studies that common neuronal need for dopaminergic stimulation. aim to investigate its potential impact on the development Nonetheless, the direction of this relationship in terms of the brain are warranted, especially when they concern of whether MPH sensitizes the subject’s brain for potential adverse consequences such as drug addiction. subsequent use of psychostimulants or constitutes a Attention deficit hyperactivity disorder is a protective tool remains a mystery. neuropsychiatric pathology with an important prevalence On one hand, some studies have assessed utilization among young people and its rate of diagnosis has of MPH as a pharmacological tool for treatment of increased by 41% over the last 10 years, with a cocaine11,12 and methamphetamine (MET)13 addictions significant increase among male adolescents aged 14 and there seems to be a consensus in the literature that to 17.3 Diagnosis of this disorder is based on persistent MPH is not a viable method for this purpose. On the other dysfunctional levels of attention, impulsivity and motor hand, other studies have been conducted to evaluate the activity (hyperactivity).4 To date there are no known capacity of MPH to elicit subsequent drug abuse. In one biological markers or laboratory tests that can confirm study, Kollins et al.14 reviewed 60 studies of humans with its presence and so the disorder is mainly identified and without ADHD diagnoses and of several animal models through observation of behavioral features.4 (e.g., rat, baboon, monkey, dog and squirrel). The aim According to the fifth edition of the Diagnostic and of that study was to evaluate the pharmacological and Statistical Manual of Mental Disorders (DSM-5),5 ADHD behavioral profiles of MPH, discussing implications for its is characterized by 18 symptoms, nine of which are potential abuse, while making a comparison with other related to inattention traits, six to hyperactivity traits psychostimulants such as cocaine and D-amphetamine. and three to impulsivity traits. The cutoff for diagnosis is Of the 60 studies reviewed, the authors asserted that 48 six traits, i.e. the number of symptoms above which the demonstrated that MPH acted in a similar way to cocaine subject is diagnosed with ADHD is six inattention traits and D-amphetamine, exhibiting reinforcing effects and and/or six hyperactivity-impulsivity traits. The cutoff for similar subjective effects in humans, assessed using self- adults is five traits. report scales. In contrast, Wilens et al.15 reviewed six The pathophysiology of ADHD is believed to be related studies using a meta-analysis approach and suggested to an abnormality within the catecholaminergic signaling that treatment with stimulants during adolescence system involving release of dopamine (DA) in areas was not associated with an increased predisposition to such as the frontal lobe and those involving the limbic abuse of a range of types of drug – including alcohol system.6 One theory postulated to explain the etiology and psychostimulants. Interestingly, that study compiled of ADHD is a fronto-striatal dopaminergic hypofunction. results that ascribed a protective component to the use Because the frontal lobe, mainly the prefrontal of stimulant medication for ADHD. Further blurring the cortex, is responsible for attentional and regulatory
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